1. Field of the Invention
The present invention relates to pharmaceutical compositions, containing 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, (S) 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole or (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, their use as pharmaceuticals for the treatment of retinal diseases, for retinal neuroprotection and vision enhancement. Three alpha-1 and three alpha-2 adrenergic receptors have been characterized by molecular and pharmacological methods. Activation of these alpha receptors evokes physiological responses with useful therapeutic actions.
2. Summary of the Related Art
Compound, 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, generically known as, medetomidine is an alpha 2 adrenergic agonist, for use in the sedation of animals. The (S) enantiomer of medetomidine, generically known as dexmedetomidine, (S) 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, is also indicated for use as a sedative or analgesic in cats and dogs administered as the hydrochloride salt. The metabolite of dexmedetomidine is (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, generically known as, OH-dexmedetomidine, is a potent pan alpha2-adrenergic agonist, activating all three alpha2 receptor subtypes. These properties are beneficial for sustained activity, particularly when the drug is delivered continuously.
Dexmedetomidine is a potent alpha2-adrenergic agonist, activating all three alpha2 receptor subtypes. It is, however, a partial agonist of the alpha2A receptor, which may result in less receptor desensitization and down regulation (shown in Table 2). It is also highly selective for the alpha2 receptor relative to alpha1-adrenergic receptor activation. The compound (5-bromo-quinoxalin-6-yl)-imidazolidin-2-ylidene-amine (structure shown below) is generically known as brimonidine tartrate and is sold under the trademark ALPHAGAN®P (available from Allergan, Inc.). Pharmacological activation of the alpha 2 adrenergic receptor by brimonidine is a well established treatment for various visual disorders of the eye.
The metabolite of dexmedetomidine is (S) [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol together with its racemic mixture, compound [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol, are described in the literature in Journal of Chromatography, (1997), 762(1+2), 281-291 by Hui, Y.-H et al.
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol is described in “Synthesis of detomidine and medetomidine metabolites: 1,2,3-trisubstituted arenes with 4′(5′)-imidazolylmethyl groups” in Journal of Heterocyclic Chemistry (1993), 30(6), (1645-1651) by Stoilov et al.

Kavanagh, et al. describe [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol in “Synthesis of Possible Metabolites of Medetomidine {1-(2,3-dimethylphenyl)-1-[imidazol-4(5)-yl]ethane” in Journal of Chemical Research, Synopses (1993), (4), 152-3.
[3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl)methanol] is described by Salonen, et al. in “Biotransformation of Medetomidine in the Rat” in Xenobiotica (1990), 20(5), 471-80.
PCT Int. Appl. WO 2010093930 A1 discloses [3-(1-(1H-imidazol-4-yl)ethyl)-2-methylphenyl]methanol and its (S) and (R) enantiomers and their use for treating pain.